instnjctions): Human structural birth defects are present in 4-5% of live births in the US, contributing to half of all pediatric hospitalizafions. Importantly, the rates are double in most of the Middle East, Central Asia and North Africa where consanguinity rates approaching 60% are the norm. Of these. Structural Brain Disorders (SBDs) are probably the single biggest component to the long-term medical complications, greatly increased morbidity and mortality. Our data demonstrate tremendous locus and genetic heterogeneity among patients with SBDs from these geographic regions, presenting both a challenge as well as an opportunity. The challenge is to derive strategies to molecularly classify pafients with these diseases. The opportunity is that these populations offer the chance to identify a much fuller picture of the genes contributing to SBDs in humans. Comprehensive discovery of mutations contribufing to SBDs holds great promise for advancing understanding of determinants of brain development and function, and its consequences including epilepsy, developmental delay, and motor deficits. The search for SBD genes has been hampered by the lack of well-characterized pedigrees to perform gene discovery. The ability to generate whole exome sequence (WES) from such pafients only increases the need for mulfiplex consanguineous pedigrees for these strategies, because the validation of potentially deleterious sequence variants (PDSV) requires segregafion analysis. Dr. Gleeson has collected probably the worid's largest cohort of such pedigrees with SBDs over the past 10 years, which will confinue in Y1-5. From these, we will perform WES on 30 probands per year in Core A, and sequence analysis in Core B. Segregation analysis in the initial family and subsequent screening in patient cohorts, both from the Gleeson lab, as well as local clinics and the massive California Birth Defects Monitoring Service will help will validate the gene's involvement in the disease. Finally, genes identified from Project 11 and III will be screened in the cohort using similar high-throughput re-sequencing strategies. In Project II and III, animal models will be created and utilized to identify underlying cellular pathophysiology, with a focus on altered cell polarity. RELEVANCE (See instructions): SBDs are a major cause of epilepsy, developmental delay and intellectual disability, and can contribute to a host of neuropsychiatric disorders. We propose to use WES to discover genes that case SBDs in a highly selected cohort of 30 independent families/year negative for mutations in known genes. Synergy with the other Projects and Cores will explore the gene's prevalence in di sease, and underlying pathogenesis.